Derivatives of the 2-(lower alkyl)-3-(lower alkyl)-4-aryl-3- or 4-cyc lohexenecarbinola

ABSTRACT

ARE DISCLOSED WHEREIN -R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to eight carbon atoms, lower alkyl of up to eight carbon atoms, and lower alkyl anilino of up to four carbon atoms; -R&#39;&#39; is selected from the group cinsisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to three carbon atoms in the alkyl portion, adamanthyl, pyridyl, furyl, lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R&#39;&#39;&#39;&#39; and R&#39;&#39;&#39;&#39;&#39;&#39; are selected from the group consisting of lower alkyl of up to three carbon atoms. These compounds exhibit estrogenic properties and when given in a single subcutaneous dose have long acting effects in the suppression of animal reproduction.   Compounds of the general formula

United States Patent 1 Karmas Sept. 11, 1973 [75] Inventor:

[73] Assignee: Ortho Pharmaceutical Corporation,

Raritan, NJ.

[22] Filed: Sept. 14, 1970 [21] Appl. No.: 72,222

Related U.S. Application Data [62] Division of Ser. No. 728,900, May 14, 1968, Pat. No.

George Karmas, Bound Brook, NJ

[52] U.S. Cl 260/482 R, 260/485 L [51] Int. Cl. ..C07c 69/40, C07c 103/14 [58] Field of Search 260/485 L, 482

[56] References Cited UNITED STATES PATENTS 2,582,253 l0/l952 Hogg et al. ..1 260/520 Primary ExaminerLorraine A. Weinberger Assistant ExaminerPaul J. Killos AttorneyNicholas A. Gallo, III et al.

[57] ABSTRACT Compounds of the general formula 3 III II 6 are disclosed wherein -R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to eight carbon atoms, lower alkyl of up to eight carbon atoms, and lower alkyl anilino of up to four carbon atoms; R is selected from the group cinsisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to three carbon atoms in the alkyl portion, adamanthyl, pyridyl, fury], lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R" and R' are selected from the group consisting of lower alkyl of up to three carbon atoms. These compounds exhibit estrogenic properties and when given in a single subcutaneous dose have long acting effects in the suppression of animal reproduction.

5 Claims, No Drawings 1 DERIVATIVES OF THE Z-(LOWER ALKYL)-3-(LOWER ALKYL)-4-ARYL-3- R 4-CYC LOHEXE'NECARBINOLA This is a division of application Ser. No. 728,900, filed May 14, 1968, now US. Pat. No. 3,557,129.

The present invention relates to compounds of the general formula III I! wherein R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to eight carbon atoms, lower alkyl .of up to eight carbon atoms, and lower alkyl anilino of up to .four carbon atoms; -R' is selected from the group consisting of alkyl and alkenyl of -up to 20 carbon atoms, cycloalkyl lower alkyl of up to three carbon atoms in .the alkyl portion, adamantyl, .pyridyl, 'furyl, lower alkyl carboxylic acids and their alkalimetalsalts, esters and carbamates; and R" and R' are selected from the group consisting of lower alkyl of up to three carbon atoms.

The compounds .of the present invention are related to the compounds disclosed in US. Pat. NO. 3,344,147 and in my copending patent applications, Ser. Nos. 662,310; 662,311; 662,295; .and 560,116. The compounds of the patentand of my copending patent applications are known to possess activity as agents for the suppression of reproduction when fed orally to animals. The compounds of the present invention are active as suppressants of reproduction not only upon oral administration but also when given parenterally and some of the compounds of the present invention can suppress 3 reproduction over a long period of time when given in only one subcutaneous injection.

These compounds are .all esters of 2-(lower alkyl)-3- (lower alkyl)-4-phenylcyclohexenecarbinol and analogs of the same and therefore may be prepared generally by the esterification of the appropriate carbinol with acids (R'COOH),acid halides (R'COCl), acid anhydrides (R'COOOCR') and ketenes In addition, the compounds may be parpared by the mono-acetylation of the primary-tertiary diol with subsequent dehydration according to the following reaction scheme:

CHZOCOR III I! The following examples illustrate the preparation of some of the compounds of the invention. While only one method of preparation is disclosed for each compound, it is to be understood that any .of the other methods noted above can also be utilized.

ALKYL ESTERS l. R HYDROGEN OR LOWER ALKYL The starting material for Examples 1 through V1 is (2-methyl-3-ethyl-4-phenyl-4- or 3-cyclohexy1-1)- methanol which is suitably prepared as described in U.S. Pat. No. 3,344,147.

EXAMPLE I (2-Meth-yl-3-ethyl-4-phenyl-3cyclohexenyl-1 )methyl Acetate A mixture of 0.35 g of -.(2-Methyl-3-ethyl-4-phenyl-3- cyclohexenyl-1)methanol and mg of p-toluenesulfonic acid in 10 ml of acetic acid is refluxed for 15 minutes and then diluted with water and extracted with hexane. The hexane solution is washed twice with d-ilute potassium carbonate, dried and evaporated. The oily residue is distilled to afford 0.30 g of the acetate, a colorless oil which boils at .8590" C at .001 mm.

Calcd. for C H O C, 79.37 H, 8.88

Found :.C, 79.14 H, 8.64 Mt max: 5.75, 8.09, 9.71, 13.17 14.26 a (neat) EXAMPLE I] (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1 )methyl Caproate A solution of 4 g of :the A -cyclohexenylcarbinol in 15 ml of dry pyridine is stirred at 0-5 C while 1 A mo- 5 lecular equivalents of caproyl chloride is added. The

resulting pasty mixture is stirred at 25 C for 15 minutes, heated at '95 C for 15 minutes, and then cooled. Five ml of water is added and the mixture stirred vigorously for 2 hours. After dilution with ml of ether, the ether phase is washed twice with cold 5 percent hydrochloric acid to remove pyridine, and then twice with cold 5 percent sodium hydroxide. The ether-solution is then dried and evaporated. The residual oil is developed on a column of alumina (neutral, W-l) prepared in benzene-hexane. Elution with benzene and ether affords the ester free of alcohol and carboxylic acid. The oily ester is distilled under high vacuum to afford the purified product, an oil which boils at 138l40 C at .002 mm.

Calcd. for C,,H,,O, :C, 80.44 H, 9.83

Found C, 80.25 ;;H, 9.81

R R 0H :1 011,011 C} 01110003 {Ill all I! Y, I

Mt max: 5.76, 8.01, 8.51, 9.07, 9.92, 13.14, 14.22 p

(neat) EXAMPLE lll (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-l )methyl Octanoate This compound is prepared following the procedure of Example 11 and using octanoyl chloride. The compound is an oil which boils at 150155 C at .001 mm.

Calcd. for C H O C, 80.85 H, 10.18

Found C, 80.66 H, 10.28 Mt max: 5.74, 8.56, 9.01, 11.79, 13.14, 14.25 u

(neat) EXAMPLE IV (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl Eicosanoate Using eicosanoyl chloride and again following the procedure of Example 11 and recrystallizing the crude solid ester from hexane (2-Methyl-3-ethyl-4-phenyl-4- cyclohexenyl-1)-methyl Eicosanoate is prepared in the form of white flakes having a melting point of 4748C.

Calcd. for C H O C, 82,38 H, 11,52

Found C, 82.25 H, 11.38 A). max. 5.74, 8.62, 11.88, 13.21 13.90, 14.22 p.

(KBr) EXAMPLE V (2-Methyl-3-ethyl-4-phenyl-4-cyclohexeny1- l)methyl 2-Ethylhexanoate A mixture of 2.0 g. of (2-Methyl-3-ethyl-4-phenyl-4- cyclohxenyl-Umethanol and 6.3 ml of a 20 percent solution of butylethyl ketene in toluene is held for 1 hour at 25 C and then for 1 hour at 100C. After the addition of methanol to destroy excess ketene, the toluene solution is evaporated and the oily residue is chromatographed on alumina (benzene-hexane elution) to isolate the crude ester. The ester is then further purified by two distillations to yield 1.7 g ofa colorless mobile oil which boils at 150l54 C at .001 mm.

Calcd. for C H O C, 81.76 H, 10.29

Found C, 81.16 H, 10.24 Mt max. 5.77, 8.52, 8.71,10.00,11.80,13.17,14.28

p. (neat) Any alkyl ester of the basic carbinol can be prepared by selecting the proper acid, acid chloride, acid anhydride or ketene. The A or A analog is prepared by utilizing the appropriate carbinol.

EXAMPLE V1 (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Benzoate This compound is prepared using benzoyl chloride in the procedure of Example 11. 1t is a colorless viscous oil which boils at 180-185 C at .001 mm.

Calcd. for C H O C, 82.59 H, 7.84

Found C, 82.38 H, 7.71 A). Max: 5.81, 7.85, 9.00 9.32, 9.72, 11.81, 13.18,

14.0 p. (neat) EXAMPLE V11 [2-Methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenyl- 1]methyl Octanoate This compound is formed from [2-Methyl-3-ethyl-4- (m-tolyl)-4-'cyclohexyl-l]methanol and octanoyl chlo ride following the procedure of Example 11. The carbino] starting material is prepared in the manner described in my copending application Ser. No. 662,31 1.

The compound is a pale yellow oil which boils at l55-l65C at .001 mm.

Calcd. for C H O C, 81.03 H, 10.34

Found C, 81.05 H, 10.36

Mt max: 5.77, 8.58, 9.03,11.81,12.8314.19 p. (neat) Esters having other lower alkyl substitution in the meta position in the phenyl ring may be prepared following the same procedure of Example 11 from the appropriate carbinol. The ortho and para analogs also may be prepared following this same procedure. The starting carbinols for the latter are prepared as described in the above-noted copending application and my copending application Ser. No. 662,310.

2. R LOWER ALKOXY EXAMPLE Vlll '[2-Methy1-3-ethyl-4-(o-anisyl)-4-cyclohexany1- llmethyl Hexanoate To a stirred solution of 3.1 g of 2-Methyl-3-ethyl-4- hydroxy-4-(o-anisyl) cyclohexanecarboxylic acid, (the preparation of which is disclosed in my copending application Ser. No. 662,295) in ml of tetrahydrofuran is added cautiously 4.0 g of lithium aluminum hydride. The reaction mixture is refluxed with stirring for one hous and then hydrolyzed in a large volume of ice and water. After acidification with dilute hydrochloric acid, the mixture is filtered, the filter cake being washed well with ether and water. Organic products in the filtrate are separated by extracting twice with ether; and the combined ether solution is then washed with dilute sodium hydroxide, dried and evaporated. The ether residue is distilled to afford 3.0 g of pale yellow glass having a boiling point of 145 C at .001 mm. This is the 1,4-diol: [2-Methyl-3-ethyl-4-hydroxy-4-(oanisyl) cyclohexanyl-l lmethanol.

Calcd: C, 73.34 H, 9.41

Found: C, 73.20 H, 9.53

)Jt max: 2.92, 8.10, 9.70, 11.00, 12.51, 13.24 p.

(KBr) A solution of 2.6 g of 1,4-diol, discribed above, and 6 m1 of hexanoic anhydride in 20 m1 of pyridine is heated at 85C for 1 9% hours, 2 ml of water added and heating continued at 85 C for one-half hour more. The solution is diluted with hexane and the hexane solution is washed with water, twice with dilute hydrochloric acid, and twice with dilute potassium carbonate. After drying and evaporation of the hexane solution,'the oily residue is distilled to afford 3.0 g of a yellow oil having a boiling point of -165 C at .001 mm. This is the ester-monoalcohol: [2-Methyl-3-ethyl-4-hydroxy-4-(oanisyl) cyclohexanyl-11methyl Hexanoate.

Calcd: C, 73.36 H, 9.64

Found: C, 74.32 H, 9.76

AA max: 2.83, 5.78, 8.10, 8.50, 9.70, 12.51, 13.23

p.(neat) A solution of 1.0 of ester-monoalcohol and 4 m1 of boron trifluoride etherate in 20 ml of ether is held at 2025 C for 5 hours and then further diluted with ether and washed twice with aqueous potassium carbonate. The ether solution is dried and evaporated and the oily residue is distilled to afiord 0.8 g. of [Z-Methyl- 3-ethyl-4-(o-anisyl)-4-cyclohexenyl-l ]methyl Hexanoate, a yellow oil which boils at l40-145 C at .001 mm.

Calcd: c, 77.05 H, 9.56

Found: C, 76.86 H, 9.39

xx max: 5.75, 8.02, 8.50, 11.82, 13.28 p (neat) Other esters of the o-anisyl series can be prepared by selecting the proper acid anhydride. In forming the psubstituted esters the starting carbinol is suitably formed according to the procedures disclosed in my copending application Ser. No. 560,116.

3. R Hydroxyl and Acyloxy EXAMPLE 1X [2-Methyl-3-ethy1-4-(p-acetoxyphenyl)-4-cyclohexenyl-1]-methyl Acetate To a stirred solution of 4.0 g of 2-Methyl-3-ethyl-4- (p-hydroyphenyl)-4-cyclohexenecarboxylic acid (prepared as described in my copending application Ser. No. 560,116) in 250 ml of tetrahydrofuran is added cautiously 7.0 g of lithium aluminum hydride. The thick mixture is stirred at 20-25 C for 20 hours and then it is hydrolyzed in a large volume of ice and water. After the mixture has been acidified with dilute hydrochloric acid, it is filtered and the filter cake is washed thoroughly with ether and water. The organic products in the filtrate are separated by two extractions with ether and then the combined ether solution is washed twice with aqueous potassium bicarbonate, dried, and evaporated to a solid residue. The latter is recrystallized from ether to afford 2.5 g of white prisms which melt at 166-167 C. This is the carbinol, [2-Methyl-3- ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl- 1]methanol:

Calcd. for C H O C, 78.01 H, 9.00

Found C, 78.01 H, 9.06 M max: 2.92, 6.61, 8.00, 8.17, 9.97, 11.76,12.10 p,

(KBr) A solution of 1.5 g of the carbinol and 7.0 ml of acetic anhydride, in 20 ml of pyridine is heated at 70 C for one-half hour and then is hydrolyzed in ice plus water. The hydrolysis mixture is extracted twice with ether and the combined ether solution is washed twice with dilute hydrochloric acid and then with aqueous potassium bicarbonate. After drying and evaporation of the ether solution, the oily residue is distilled to afford 1.6 g of [2-Methyl-3-ethyl-4-(p-acetoxypheny1)-4- cyclohexenyI-1-1-methyl Acetate, a colorless oil which boils at 135l40 C at 0.001 mm.

Calcd. for C H O C, 72.70 H, 7.93

Found C, 72.44 H, 8.00 M max: 5.68, 5.74, 7.30, 8.33, 9.68, 9.80, 10.97,

11.83 p, (neat) Other di-esters of the para-hydroxy phenyl carbinols may be prepared by selecting the proper acid chloride.

EXAMPLE X [2-Methyl-3-ethyl-4-(p-hydroxyphenyl)4-cyclohexeny1-1]-methyl Acetate.

This and othe hydroxy derivatives are obtained from the appropriate di-esters which are in turn prepared as described in Example IX.

A mixture of 1.0 g of the diacetate, 0.8 g of potassium bicarbonate, ml of water, and 17 ml of methanol is refluxed for five minutes and then diluted with cold water. The organic material is extracted with an etherhexane mixture which is dried and evaporated to an oily residue which slowly crystallizes. This crude monoacetate is recrystallized from hexane containing 5 percent ether to afford 0.5 g of [2-Methyl-3-ethyl-4-(phydroxyphenyl)-4-cyclohexenyl-1]methyl Acetate in the form of white prisms which melt at 6772 C.

Calcd. for C H O C, 74.97 H, 8.39

Found C, 75.74 H, 8.68

Mt max: 2.89, 5.81, 6.61, 7.90, 9.68, 11.76, 11.91 p.

(KBr) EXAMPLE XI [2-Methyl-3-ethyl-4-(p-isobutyryloxyphenyl)-4- cyclohexenyl-l l-methyl Acetate Where the acyloxy group is different from the ester group, the compound is produced from the phydroxyphenyl mono ester obtained as described in Example X.

A solution of 0.35 g of the phenolic monoacetate and 2.5 ml of isobutyric anhydride in 15 ml of pyridine is held at 25 C for 3 hours and then hydrolyzed by stirring with water for 1 hour. The product is extracted with hexane and the hexane solution is washed with dilute hydrochloric acid and with potassium carbonate. After drying and evaporation of the hexane solution, the residue is distilled to afford 0.35 g of [2-Methy1-3- ethyl-4-(p-isobutyryloxyphenyl)-4-cyclohexeny1- 1 ]methyl Acetate, a colorless oil which boils at 1451 50 C at .001 mm.

Calcd. for C H O, C, 73.71 H, 8.44

Found C, 73.58; H, 8.48 Mt max: 5.70, 5,75, 8.10, 8.31, 8.57, 8.81, 9.69,

10.90, 11.48, 11.80 p. (neat) 4. R ANILINO EXAMPLE Xll [2-Methyl-3-ethyl-4-(p-dimethylanilino)-3and 4-cyclohexenyl-l ]-methyl Valerate This compound is prepared from 2-Methyl-3-ethyl-4- (p-dimethylanilino)-3 and 4-cyclohexenecarboxylic acid which is prepared as described in my copending patent application Ser. No. 662,311.

To a stirred solution of 3.0 g of the inseparable mix: ture of 2-Methyl-3-ethyl-4-(p-dimethylanilino)-3 and 4-cyclohexenecarboxylic acids in ml of tetrahydrofuran is added cautiously 3.0 g of lithium aluminum hydride. The mixture is stirred at 25 C for 20 hours and then it is hydrolyzed in a large volume of ice and water. This hydrolysis mixture is filtered and the filter cake is washed thoroughly with ether. The product is isolated by two extractions of the filtrate with ether and the combined ether solution is dried and evaporated. The oily ether residue is distilled to afford 2.5 g of a very viscous yellow oil which boils at 145 C a 0.001 mm. This is the carbinol mixture, [2-Methyl-3-ethyl-4- (p-dimethylani1ino)-3 and 4-cyclohexenyl-l methanol:

Calcd. for C H ON C, 79.07 H, 9.95

Found C, 79.08 H, 9.91 M max: 2.99, 6.20, 6.59, 7.40, 9.42, 9.70, 9.91,

10.58, 12.29 p. (neat) A solution of 1.0 g of the mixed carbinol described above and 20 ml of pyridine is stirred and cooled in an ice bath while 3 ml of valeryl chloride is added. The dark mixture is held at 20 for 3 hours and then it is hydrolyzed by stirring with water and hexane for 1 hour. The hexane layer is separated and is washed twise with dilute sodium hydroxide, dried, nd evaporated. The

oily residue is developed onto a chromatographic column of neutral alumina, and elution with ether affords the crude ester. Distillation of the ester gives the mixture of [2-Methyl-3-ethyl-4-(p-dimethylanilino)3 and EXAMPLE XIV [2-Methyl-3 -e thy1-4-( p-anisyl )-4-cyclohexenyl- -1]methyl l-Adamantoate V This compound is prepared from [2-Methyl-3-ethyl- 4-(p-anisyl)-4-cyclohexenyl-1lmethanol and Adamantoic acid chloride following the procedure. of Example II. It is a viscous oil which boils at 200220 C at .002 v Calcd. for C ,,H O C, 79.58 H, 9.06

Found C, 79.23 H. 9.09 AA max: 5.80, 8.01-8.12, 8.42, 9.02, 9.24 9.60, 11.93,

13.50 p. (neat) CYCLOALKYL LOWER ALKYL ESTERS EXAMPLE XV [2-Methyl-3-ethyl-4-(p-anisyl)-3-cyclohexenylllmethyl B-Cyclopentylpropionate This compound is formed from cyclopentylpropionic acid chloride and [2Methyl-3-ethy1-4-(p-anisyl)-3 cyclohexeny1-1]methanol according to the procedure of Example 11. The compound is an oil which boils at 160-170 C at 0.001 mm.

Calcd. for C H O C, 78.08; H, 9.44

Found C, 78.04 H, 9.49 AA max: 5.75, 8.01, 8.49, 9.61, 12.04 p. (neat) NMR (CDCl;,) 0.73, 0.84, 0.96, 0.90, 1.01

FUROATES AND NICOTINATES EXAMPLE XVI (2-Methyl-3-ethyl-4-phenyl-4-cyc1ohexenyl-l )methyl Nicotinate I This compound is prepared using nicotinoyl chloride following the procedure of Example II but omitting the HCl washing. It is a yellow oil which boils at 175180 C at 0.001 thin. I t

Calcd. for c,,1i,,o,N C, 78.77 H, 7.51

Found C, 78.54; H, 7.57

AA max: 5.79, 7.78, 8.81, 8.95, 9.73,1l.80,13.15,1-

3.50, 14.27 p. (neat) EXAMPLE XVII (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-l )methyl 2-Furoate This compound is prepared generally following the procedures of Example 11 and using 2-furoyl chloride to afford white granules which melt at 72 C.

Calcd. for C ,H 0 C, 77.75 H, 7.46

Found C, 77.81 H, 7.54 AA max: 5.86, 7.70, 8.56, 9.00, 11.83, 12.92, 13.17,

14.30 (KBr) Other Miscellaneous Esters of the Carbinols Including Esters with Dibasic Acids, Unsaturated Acids, Etc.

EXAMPLE XVIII (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Hemisuccinate A solution of 3.1 g of the carbine] and 9.0 g of succinic anhydride in 60 ml of pyridine is heated at 95 C for 1 hour, then 9 ml of water is added and heating is continued for 15 minutes longer. The mixture is diluted with hexane and the hexane solution washed four times with water to remove succinic acid, dried and evaporated. Distillation of the oily residue affords 3.4 g of the hemisuccinate, a viscous colorless oil which boils at- 180-190 C-at 0.001 mm. Calcd. for C, H,,O, C, 72.70 H, 7.93

Found C, 72.61 1-1, 8.05 AA max: 5.77, 5.83, 8.57, 10.03, 11.82, 13.17, 14.28

p. (neat) EXAMPLE XIX (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Succinamate 1.0 g of the compound of Example XVIII and 8 ml of thionyl chloride is refluxed for 20 minutes, diluted with 20 ml of toluene, and evaporated to afford an oily residue of the ester acid chloride. The latter is dissolved in 20 m1 of cold dioxane and this solution is treated with 4 ml of 28 percent aqueous ammonia. After a period of 1 hours at 20 C this reaction mixture is diluted with water and extracted with ether. The ether solution is washed with water, dried and evaporated. The residue is recrystallized from ether to afford 0.68 g of the ester amide, white prisms which melt at 9091 C.

Calcd. for C H O N C, 72.92 H, 8.26 I

Found C, 72.77 H, 8.44 AA max: 2.95, 3.11, 5.78, 5.97, 7.42, 8.49, 10.12,

11.88, 13.20, 14.23 p. (KBr) EXAMPLE XX EXAMPLE XXI (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-l )methyl Succinate This compound is prepared utilizing succinyl chloride and following the procedure of Example 11. The product is purified by chromatography on alumina to yield a yellow oil.

Calcd. for C l-1 0, C, 79.66 H, 8.54

Found C, 80.61 H, 9.06

M max: 5.75, 8.60, 9.96, 10.13, 13.17, 14.27 a

(neat) EXAMPLE XXII (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1 )methyl IO-Undecenoate A This compound is prepared using undecenoyl chloride and following the general procedure of Example 11 to yield a colorless oil which boils at l75l80 C at .001 mm.

Calcd. for C H o, 2 C, 81.76 H, 10.17

Found C, 81.68 H, 10.23 M max: 5.75, 8.52, 10.00, 11.00, 13.18, 14.27

(neat) While the preparation of only some of the compounds of this invention has been specifically described, one skilled in the art should be able to prepare the remainder of the compounds following the general techniques set forth.

As mentioned previously, the compounds of this invention exhibit anti-littering effects when given orally or parenterally and are estrogenic agents to varying degrees.

Estrogenic effects are measured against the estrogenic effects of estradiol as a standard. In carrying out the test, female rats of a Wistar-derived strain are bilaterally ovariectomized under light ether anesthesia. About a week following surgery all animals are given a priming dose of 2-1 pg estradiol-17B by subcutaneous injection and vaginal smears are taken on each :of the next two days. Animals which do not show vag inalcornification are rested a week and reprimed. Rats which respond positively to the priming injection are rested a week and then given a single subcutaneous injection of the test material in sesame oil. Vaginal smears are taken daily to assess the duration of estrogenic re- 5 sponse (vaginal corniflcation) in each animal as opposed to the vaginal cornification induced by the priming. The results, tabulated in Table l, for certain of the compounds prepared according to the examples hereinbefore set out show that the compounds of this invention have substantial estrogenic activity.

The parenteral anti-littering properties of the compounds are measured by administering to adult female rats of Wistar-derived strain a single subcutaneous injection of the test material in sesame oil. Controls receive sesame oil vehicle only. Ordinarily twenty animals are assigned to each group.

Both groups are cohabitated with adult male rats i the ratio of three males per five females starting on the day of treatment. Rats are examined twice weekly for gross signs of pregnancy. Gravid animals are removed and allowed to deliver so that a count of young and their condition may be recorded. The mean interval between drug administration (and cohabitation) and conception is calculated for each group using an average gestation length of 21 days.

Cohabitation is counted for 90 days or until 80 percent of the females become pregnant, whichever occurs sooner.

The minimum dosage is mg/Kg body weight required to prevent littering in the rats for various compounds, the preparation of which was specifically described in the examples, is set out in Table I. The actual effects of some of the compounds on littering at various dosage levels is set out in Table 11.

CH;OfiR

Pharmacological activity Antl- Estrogenic littering R A (times EE) parenteral -CH3 3 CH.-; 4 2.4 -2-5 mg. C5Hn 3 1/4 mg. -C5H11 4 C7Hts 4 1.7 1mg. C10Hu 4 0.50

(12115 4 0.70 -2.5 mg. Ant-elm c1m, 4 0.20 CsH5 4 1.2 5mg. C5Hn 4 0.07

X p-OH CH: 4

C4H 3 and 4 0.001 Adamautyl-l 3 1.2 1mg. do 4 2/3 2.5 mg.- ....do 4 4/3 1mg.

3 2 1mg. cmcm :l

Pyrldyl-3 4 0.80 Furyl-2 4 0.80 -CHQCHiCONH: 4 1.4

e 290 da.

'IA B LE 11 Mean value day Littcrs/ pregnancy occurred number Days (omponml Dose, N nmhor ruts Exporlcof .l'lxmnpln m g/kg. control experimental Control mental habltatcd III 0. 1 10/10 9/10 10. 3 7. 3 27 1. 0 10/10 /10 10. 3 50. 5 90 XIIIA 0. 5 16/20 5/20 4. 7 7. 9 33-34 1. 0 16/20 16/20 4. 7 7. 1 33-62 2. 5 19/20 3/20 5. 9 15. 0 90 5. 0 10/10 0/10 15 XIII 0.5 9/10 8/10 6. 2 6. 8 27 1. 0 16/20 10/20 5. 6 12. 7 27-90 2. 5 7/10 0/10 90 XIV 0. 1 10/10 10/10 10. 3 8. 9 27 1. 0 10/10 10 10. 3 33. 7 90 What is claimed is: 1. Compounds of the formula boirylic zzidsarid theirailiali metal saltsjlower alkyl esters and amides; and R and R' are selected from the group consisting of lower alkyl of up to three carbon atoms.

2. (2-Methyl-3-ethyl-4-phenyl 4-cyclohexenyl-l methyl Hemisuccinate of claim 1.

3. (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-l methyl Succinamate of claim 1.

4. (Z-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-l methyl Ethyl Succinate of claim 1.

5. (2-Methyl-3-ethyl-4-phenyl-3-cyclohexe methyl Succinate of claim 1.

722 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,758, 552 Dated September ll, 1973 Inventor) George Karmas It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

r- In the Abstract, line 6, "cinsisting" should read consisting .1

In the Abstract," line 9, adamantl'lyl should read adamantyl In Column 1., line 18, "parpared" should read prepared In Column 2, lino ll, "cyclohexyl" should read cyclohexenyl In Column 3,1166 25, "82,38 and 11,52" shouldread,-=-,82.38-and 11.52

In Column 3, 7 line 1+9, 2 should read 3 In Column 3, line 67, "cyclohexyl" should read cyclohexenyl In Column line 21, "cyclohexanyl" should read cy'clohexenyl In Column L "line- 29, "hous" should read hour In Column line 37, "of pale yellow" should read of a pale yellow In Column A, line 62, "of 1.0" should read of 1.0 In Column 6, line '68, "twise" should read twice In Column 6, line 69, "nd" should read and In Column 7, line 8, "77.36" should read 77.26

In Column 10, line 26, "counted" should read contiz nied In Column 10, line 29, "is" should read in UNITED STATES PATENT OFFICE Page 2 CERTIFICATE OF CORRECTION 3,758,55 Dated September 1973 George Karmss Patent No.

Inventor(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In claim 1, line 33, "is" should read of Signed and sealed this 18th day of June 197 (SEAL) Attes't: O

EIMARD M.FLETGHER,JR. v CQHARSHALL DANN Commissioner of Patents Atbesting Offioer USCOMM-DC 60S76-P69 1 us. covuuulm' PRINTING olrlc: "II o-au-su.

FORM PO-1 050 (10-69) 

2. (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)-methyl Hemisuccinate of claim
 1. 3. (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)-methyl Succinamate of claim
 1. 4. (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)-methyl Ethyl Succinate of claim
 1. 5. (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1)-methyl Succinate of claim
 1. 